Constitutive Expression of phVEGF ₁₆₅ After Intramuscular Gene Transfer Promotes Collateral Vessel Development in Patients With Critical Limb Ischemia

Abstract

These findings may be cautiously interpreted to indicate that intramuscular injection of naked plasmid DNA achieves constitutive overexpression of VEGF sufficient to induce therapeutic angiogenesis in selected patients with critical limb ischemia.

Development of safe and efficient novel nonviral gene transfer using ultrasound: enhancement of transfection efficiency of naked plasmid DNA in skeletal muscle

“…The clinical utility of gene therapy using the VEGF gene has been recently reported for the treatment of critical limb ischemia and myocardial ischemia. [4][5][6][7][8][9][10][11] Instead of VEGF, other angiogenic growth factors such FGF, HGF and a transcription factor for angiogenesis, HIF (hypoxiainducible factor), have been considered candidates for therapeutic angiogenesis as gene therapy for the treatment of patients with critical limb ischemia. [12][13][14][15][16][17][18][19][20] Although the feasibility of therapeutic angiogenesis using these angiogenic growth factors has been reported in experimental models and human clinical trials, [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] there are still unresolved problems such as undesirable side-effects.…”

“…1 Therefore, novel therapeutic modalities are needed to treat these patients. Recently, the efficacy of therapeutic angiogenesis using VEGF (vascular endothelial growth factor) gene transfer has been reported in human patients with critical limb ischemia [4][5][6][7] and myocardial ischemia. [8][9][10][11] In addition to VEGF, the utility of gene transfer of other angiogenic growth factors such as fibroblast growth factor (FGF) or hepatocyte growth factor (HGF) has been reported to stimulate collateral formation.…”

“…Interestingly, most successful clinical trials of treating peripheral arterial disease using angiogenic growth factors have been performed by intramuscular transfection of naked plasmid DNA, [4][5][6][7][8] although in vivo gene transfer using direct injection of 'naked' DNA into cardiac and skeletal muscle is inefficient. It is apparent that a more efficient gene transfer method is required to achieve therapeutic effects.…”

Angiogenesis induced in muscle by a recombinant adenovirus expressing functional isoforms of basic fibroblast growth factor

“…A phase I clinical trial in patients with critical limb ischemia indicated that intramuscular gene transfer of naked plasmid DNA encoding VEGF 165 is sufficient to induce therapeutic angiogenesis. 7,38 Recombinant adenoviruses have been recently used to transfer different genes coding potent angiogenic factors. Angiogenesis was evaluated with a recombinant Ad expressing aFGF or VEGF either mixed with Matrigel and injected in subcutaneous position or after injection in rat adipose tissue.…”

Recombinant AAV vector encoding human VEGF165 enhances wound healing

“…Inoculation of AAV-VEGF165 resulted in the increase (approximately three-fold) of ␣-SMA-positive vessels (Figure 3), an observation which further corroborates the in vivo angiogenetic potential of VEGF gene transfer. [35][36][37] Seventeen Wistar rats were evaluated for the efficacy of AAV-VEGF165 transduction to improve wound healing. In each animal, three full thickness excisional wounds were produced, and treated with between five and seven injections (100 l total) of phosphate buffered saline (mock), AAV-LacZ, or AAV-VEGF165 (1 × 10 12 viral particles/ml each).…”